Hypothalamic Glutamate/GABA Cotransmission Modulates Hippocampal Circuits and Supports Long-Term Potentiation.

Musa Iyiola Ajibola,Cheng-Chang Lien,Jei-Wei Wu,Wahab Imam Abdulmajeed

doi:10.1523/jneurosci.0410-21.2021

Musa Iyiola Ajibola, Cheng-Chang Lien + Show 2 more

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https://doi.org/10.1523/jneurosci.0410-21.2021

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Abstract

Subcortical input engages in cortico-hippocampal information processing. Neurons of the hypothalamic supramammillary nucleus (SuM) innervate the dentate gyrus (DG) by coreleasing two contrasting fast neurotransmitters, glutamate and GABA, and thereby support spatial navigation and contextual memory. However, the synaptic mechanisms by which SuM neurons regulate the DG activity and synaptic plasticity are not well understood. The DG comprises excitatory granule cells (GCs) as well as inhibitory interneurons (INs). Combining optogenetic, electrophysiological, and pharmacological approaches, we demonstrate that the SuM input differentially regulates the activities of different DG neurons in mice of either sex via distinct synaptic mechanisms. Although SuM activation results in synaptic excitation and inhibition in all postsynaptic cells, the ratio of these two components is variable and cell type-dependent. Specifically, dendrite-targeting INs receive predominantly synaptic excitation, whereas soma-targeting INs and GCs receive primarily synaptic inhibition. Although SuM excitation alone is insufficient to excite GCs, it enhances the GC spiking precision and reduces the latencies in response to excitatory drives. Furthermore, SuM excitation enhances the GC spiking in response to the cortical input, thereby promoting induction of long-term potentiation at cortical-GC synapses. Collectively, these findings provide physiological significance of the cotransmission of glutamate/GABA by SuM neurons in the DG network.SIGNIFICANCE STATEMENT The cortical-hippocampal pathways transfer mnemonic information during memory acquisition and retrieval, whereas subcortical input engages in modulation of communication between the cortex and hippocampus. The supramammillary nucleus (SuM) neurons of the hypothalamus innervate the dentate gyrus (DG) by coreleasing glutamate and GABA onto granule cells (GCs) and interneurons and support memories. However, how the SuM input regulates the activity of various DG cell types and thereby contributes to synaptic plasticity remains unexplored. Combining optogenetic and electrophysiological approaches, we demonstrate that the SuM input differentially regulates DG cell dynamics and consequently enhances GC excitability as well as synaptic plasticity at cortical input-GC synapses. Our findings highlight a significant role of glutamate/GABA cotransmission in regulating the input-output dynamics of DG circuits.

Highlights

The cortical-hippocampal pathways transfer mnemonic information during memory acquisition and retrieval and play a central role in spatial navigation, declarative memory, and complex information processing (Morris et al, 1982; Squire, 1992; Henze et al, 2002; Amaral et al, 2007; Nakashiba et al, 2012; Buzsáki and Moser, 2013; Ito et al, 2018; Hainmueller and Bartos, 2020)
Given that the supramammillary nucleus (SuM) input preferentially excites dendrite-targeting INs (D-INs), we investigated whether synapse-specific excitation and inhibition correlate with differential recruitment of dentate gyrus (DG) cells
We found that photostimulation of SuM input (5 ms, 470 nm, 5 Hz light pulses) in the DG evoked fibers in the granule cell layer (GCL) and sequentially recorded biocytin-filled mossy cells (MCs) #1, MC #2, and a granule cells (GCs)

Summary

Introduction

The cortical-hippocampal pathways transfer mnemonic information during memory acquisition and retrieval and play a central role in spatial navigation, declarative memory, and complex information processing (Morris et al, 1982; Squire, 1992; Henze et al, 2002; Amaral et al, 2007; Nakashiba et al, 2012; Buzsáki and Moser, 2013; Ito et al, 2018; Hainmueller and Bartos, 2020). The synapses present along this pathway have been characterized extensively as substrates for distinct types of memories (O’Keefe and Dostrovsky, 1971; Nakazawa et al, 2002; Remondes and Schuman, 2004; Kitamura et al, 2015). The granule cells (GCs), the principal cells of the dentate gyrus (DG), receive cortical inputs (Buckmaster et al, 1996; Scharfman and Myers, 2012; Zhang et al, 2013) and segregate them into distinct neural codes. Subcortical inputs from different areas of the brain innervate GCs (Nyakas et al, 1987; Nitsch and Leranth, 1994; Unal et al, 2015). Information regarding the synaptic organization and functions of the subcortical inputs is relatively limited

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